The present invention concerns methods of making functional biodegradable materials, and their biomedical applications.
As used herein, biodegradable polymers are as polymers which are degradable in a physiologically relevant environment, either by hydrolysis, by enzymatic reactions or by other mechanisms, to produce biocompatible or non-toxic by products (see also Chih-Chang Chu, “Biodegradable Polymeric Biomaterials: An Overview”, in J D Bronzino, editor-in-chief, The Biomedical Engineering Handbook, CRC Press, 1995; Yichun Sun et al., “Biodegradable Polymers and Their Degradation Mechanisms”, American Pharmaceutical Reviews, 2001, 4(3), 9–18).
Typical examples of natural biodegradable polymers include proteins and polysaccharides such as gelatin, albumin, collagen, starch, detrxan, chitosan and chitin. Typical examples of synthetic biodegradable polymers include polylactic acid, polyglycolic acid, and their copolymers, and the current invention mainly concerns the functionalization of synthetic biodegradable polymers. More information on the making of synthetic biodegradable polymers can be found in Masahiko Okada, “Chemical Synthesis of Biodegradable Polymers”, Progress in Polymer Science, 2002, 27, 87–133.
The biomedical use of biodegradable polymers is believed to have begun in the 1970s with the first biodegradable sutures prepared from copolymers poly(lactic-co-glycolic acid) (PLGA). Since then, numerous applications in the biomedical field have been made including uses such as wound closures, body implants, tissue engineering materials, and drug delivery materials.
The commonly-used biodegradable polymers such as poly(lactic-co-glycolic acid) and polycaprolactone, as linear aliphatic polyesters, don't contain functional groups such as carboxylic acid groups, hydroxyl groups and amine groups, except at the polymer chain ends. This lack of functional groups greatly limits the application of these synthetic biodegradable polymers. Functional groups containing reactive sites could, for example, bind to biologically active compounds such as peptides in order to help direct cell behavior in a tissue engineering matrix. As another example, the reactive sites could be used to bind drugs, thus making prodrugs and novel drug delivery systems. As yet another example, the incorporated functional groups make further chemical modification much easier, enabling additional properties to be added to the biodegradable polymer such as, for example, making them hydrophilic and water dispersible, and making it possible to have water-based preparation process.
Known methods for the introduction of functional groups into biodegradable polymers are: (1) incorporating special functional monomers at the beginning of the preparation of biodegradable polymers, (2) using reactions through carboxyl acid and hydroxyl groups at the chain ends and (3) using functional polymers as the ring-opening polymerization initiators in the making biodegradable polymers. Representative examples of these three approaches are:
(1) Via the Incorporation of Special Monomers
Copolymers with pendant carboxyl groups were prepared by copolymerization of L-lactide and 3-(S)-[benzoyloxycarbonyl]-methyl]-1,4-dioxane-2,5-dione (BMD), a novel cyclic di-ester monomer consisting of both glycolate and benzyl-α-L-malate units. The copolymerization was carried out in bulk, with stannous 2-ethylhexanoate as catalyst. (see, for example, T. Yamaoka and Y. Kimura, “Biodegradable Copolymers”, in J C Salamone edited Concise Polymeric Materials Encyclopedia, page 109–111, CRC Press, Boca Raton, 1998). The resulting polymers can only have one pendant carboxyl group for each BMD monomer used, and the making requires a new di-ester monomer from the beginning of ring-opening polymerization and the removal of the benzoyloxy groups to display the pendant carboxyl group.
U.S. Pat. Nos. 5,399,665 and 5,654,381 and D A Barrera et al., Macromolecules, 1995, 28, 425–432 and J S Hrkach et al., Macromolecules, 1995, 28, 4736–4739 disclosed the making of biodegradable polyesters incorporated with specially-designed lysine residue monomers in the ring-opening polymerization, and also the use of the ε-amine groups in the amino acid residues of these polymers as ring-opening initiators to react with amino acid N-carboxyanhydrides (NCAs) to graft poly(amino acid) chains onto the biodegradable polymers.
(2) Via Reaction at the Chain End:
E B Lavik et al. in Journal of Biomedical Materials Research Applied Biomaterials, 2001, 58, 291–294, disclosed the making of block copolymer of PLGA (poly(lactic-co-glycolic acid)) and polylysine by direct coupling of protected polylysine (poly-ε-carbobenzoic-lysine) with carboxylic-acid-ending PLGA polymer, followed by the removal of the protection groups from the polylysine blocks.
WO 00/60956 (C. -Y. Won et al.) and Y. Zhang et al., Journal of Polymer Science A: Polymer Chemistry, 1999, 37, 4554–4569 disclose the modification of PLGA polymers by first adding vinyl groups at their chain ends, and then reacting the modified polymers with vinyl-group-incorporated polysaccharides such as dextran. The resulting network then has both hydrophilic and hydrophobic components.
M. Furch et al. in Polymer, 1998, 39, 1977–1982 describes the synthesis of copolymers of polyglycolide and methyl acrylate (PMA-g-PGA), by firstly making vinyl-group-ending polyglycolide macromonomers, which in turn was made by HEMA (2-hydroxylethy methacrylate)-initiated ring-opening polymerization of glycolide. In the same paper, they mentioned that copolymers of polylactide with vinyl pyrrolidone and N,N′-dimethyl-acrylamide co-monomers. H. Shinoda and K. Matyjaszewski in Macromolecules, 2001, 34, 6243–6248 describe the making of poly(methyl methacrylate)-g-poly(lactic acid) (PMMA-g-PLA) by a similar procedure but through the atom transfer radical polymerization.
(3) Via the Use of Polyols as the Polymerization Initiators:
Block copolymers of PLGA and poly(ethylene glycol) (PEG) have been discussed in the literature by J L Hill-West et al., in the Proceeding of National Academy of Science USA, 1994, 91, 5967–5971; by J L West et al., Proceeding of National Academy of Science USA, 1996, 93, 13188–13193; by B. Jeong et al., Nature, 1997, 388, 860–862; by B Jeong et al., Macromolecules, 1999, 32, 7064–7069; by T. Riley et al., Langmuir, 2001, 17, 3168–3174; and by T. Kissel et al., Advanced Drug Delivery Reviews, 2002, 54, 99–134. These copolymers include PLGA-PEG, PLGA-PEG-PLGA and PEG-PLGA-PEG types, and are mainly made by PEG-initiated ring-opening polymerization of cyclic esters.
B. Jeong et al., in Macromolecules, 2000, 33, 8317–8322, also discloses the making of graft copolymers PEG-g-PLGA with PEG as the backbone chains and PLGA as the side chains. The grafting reaction was made possible by first incorporate pendanthydroxyl-group-bearing units in the backbone chains and later used these modified PEG chains to ring-opening polymerize lactide and glycolide monomers.
The use of poly(propylene glycol) (PPG) instead of PEG as the initiators for ring-opening polymerize lactide resulted in polylactide-PPG-polylactide tri-block copolymers, was disclosed by T. Yamaoka and Y. Kimura in “Biodegradable Copolymers”, in Concise Polymeric Materials Encyclopedia, page 109–111, CRC Press, Boca Raton, 1998. It should be noted that the use of PEG and PPG as polymer initiators, though it may change the hydrophilicity of the final polymers, doesn't introduce functional groups in the biodegradable polymers.
U.S. Pat. No. 5,929,196, Y. Li et al. in Polymer, 1997, 38, 6197–6206; Y. Li et al. in Polymer, 1998, 39, 3087–3097; and A. Breitenbach et al., in Polymer, 2000, 41, 4781–4792 describe the making of graft copolymers with PLGA as side chains and polyols as the backbone chains. Their polyols include both neutral polymers such as poly(vinyl alcohol)s and polyelectrolytes such as dextran sulfate sodium, diethylaminoethyl dextran chloride, and also copolymers of poly(vinyl alcohol) and poly(β-methacrylic acid). The copolymers were made by ring-opening polymerization of cyclic ester monomers, with the hydroxyl groups in the polyol backbone chains as the initiators.
An exception to the above-mentioned approaches can be found in U.S. Pat. No. 5,610,241, which discloses the modification of biodegradable polymers such as Poly-DL-lactic acid with side chains of amino acid groups such as L-lysine, where the starting biodegradable polymers have repeating units consisting of carbonyl groups and hydrogen atoms on the carbon on the α position to the carbonyl group. The modification was done first by reacting the starting biodegradable polymers with a base such as alkali metal alkoxides, to form carbon ions on the α-carbon of the carbonyl groups in the repeating units (—CHR—C(═O)— to —C—R—C(═O)—); and then react the carbon-ion-bearing polymers with protected reactive amino acids, followed by the de-protection of side chain groups. The formation of carbon ions in the biodegradable polymers involves low temperature such as −78° C.
As is apparent to those skilled in the art, the known methods to functionalize biodegradable polymers use complicated chemistry and chemical processes. They either use specially designed monomers or multi-step reactions, or extreme reaction conditions. There is a great need to develop a simple and versatile method to make functional biodegradable polymers.